Cytoadhesion of Plasmodium falciparum infected erythrocytes is a major virulence determinant that enables parasites to sequester from blood circulation by binding to the endothelial lining of blood vessels and avoid spleen-dependent killing mechanisms. Whereas infected erythrocytes sequester in a variety of microvascular beds, cerebral malaria is a life-threatening disease complication that is associated with massive sequestration in brain microvessels. Cerebral malaria is accompanied by endothelial activation, blood-brain barrier disruption and fibrin thrombi at sites of infected erythrocyte sequestration. While progress has been made in understanding the binding properties of infected erythrocytes, critical questions remain unanswered about the mechanisms of cerebral malaria pathogenesis. Binding of P. falciparum- infected erythrocytes is mediated by the large and diverse P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We recently showed that severe malaria is associated with a distinct subset of PfEMP1 variants that binds to endothelial protein C receptor, an important regulator of blood clotting and endothelial activation. Our preliminary findings suggest that parasites may impair EPCR function and lead to cerebral malaria complications. However, a significant barrier to investigating disease mechanisms in human cerebral malaria is the inaccessibility of the brain. This project will exploit new advances in microvascular engineering technology in the study of human cerebral malaria. By building a human brain microvascular model, we will: 1. Characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to human brain endothelial cells and other microvascular beds using in vitro 3D human microvascular systems. 2. Determine the consequent changes on the barrier and thrombogenic properties of the vessel wall. 3. Determine host signaling pathways engaged by the infected erythrocyte-endothelial activation that are associated with endothelial dysfunction or protection. The success of the project will shed light on the pathogenic mechanisms associated with cerebral malaria and may guide potential therapeutic development.